Bisphosphonates and their impact on disseminated tumor cells in early stage breast cancer

Abstract

Bone is the most common site of relapse in breast cancer. Unlike many other malignancies, breast cancer is often associated with late-onset metastases, most commonly seen in bone and soft tissue. Pre-clinical and clinical evidence suggest that micrometastases occur at a very early stage of cancer development but do not become overt metastases until a later time when the microenvironment is more suitable. Bisphosphonates (BPs), especially zoledronic acid (ZOL), decrease bone resorption by suppressing the activity of osteoclasts and are used to prevent further bone loss in patients with osteoporosis. In addition, pre-clinical and clinical evidence suggest that potent BPs have direct and/or indirect anti-tumor effects, through induction of apoptosis, inhibition of invasion and metastases as well as angiogenesis, and through alteration of the immune system. ZOL is approved for the treatment of metastatic cancer to bone, and has been shown to prevent skeletal related events and reduce associated pain, without a clear impact on survival. Several large clinical trials (ABSCG 12, ZO-FAST and AZURE) have studied the direct anti-tumor effect of BPs in early stage breast cancer. The results are controversial, suggesting that ZOL may have benefits in specific settings. Targeting patients at particularly high risk for relapse, and identifying surrogate markers of BP effect is clearly a critical component necessary to understand the anti-tumor effect of these agents. Disseminated tumor cells (DTCs) are surrogate markers that have been correlated with an increased risk of recurrence in patients with early stage breast cancer. Several studies have either used the presence of DTCs to assess risk and determine eligibility for BP treatment, or have used DTCs as a surrogate marker of BP anti-tumor effect. This review summarizes the pre-clinical data supporting anti-tumor effects of BPs as well as their impact on DTCs in clinical studies. New candidates for bone-targeted therapy are briefly discussed.